Amphiphilic Lipid Compound Which Contains Zinc(ii)-Dipicolylamine Complex for Nucleic Acid Binding and Lipid Nanoparticle Composition Comprising the Same

This application claims the benefit of Korean Patent Application No. 10-2024-0048598 filed on Apr. 11, 2024, in the Korean Intellectual Property Office, the entire disclosure of which is incorporated herein by reference for all purposes.

The present disclosure relates to an amphiphilic lipid compound which contains Zn(II)-dipicolylamine complex (Zn/DPA) for nucleic acid binding and lipid nanoparticle composition for nucleic acid delivery comprising the same.

Nucleic acid-based drugs, which began more than 40 years ago by injecting plasmid DNA into the human body to aid production of deficient proteins, have since been reported in various types such as antigens, decoys, antisense, siRNAs, and miRNAs that suppress the transcription and translation of genes. The nucleic acid-based drug has been attracting attention as a personalized therapeutic agent through complementary binding with DNA or RNA with a specific sequence by targeting DNA or RNA rather than proteins. The nucleic acid-based drug is utilized not only as a therapeutic agent but also as a prophylactic agent that defends against diseases through injection of genes capable of expressing antigens against specific diseases. While gene-based vaccines are divided into DNA vaccines, RNA vaccines, and viral vector vaccines, the RNA vaccine thereamong takes effects by injecting mRNA coding an antigen into the human body to express antigens and induce formation of antibodies against the antigen in vivo, and since there is no potential risk of infection by viral vector-based vaccines or genetic mutations by DNA vaccines, with an advantage of quick development, it has been in the spotlight as an effective measure for COVID-19 that broke out in 2019.

However, the nucleic acid-based drug is easily degraded by nucleases in the human body with poor delivery into cells as it is a negatively charged macromolecule, such that there is a need for a method to deliver the drug to a desired spot in a stable and efficient way. While delivery techniques based on various materials such as lipids, polymers, dendrimers, and inorganic metallic materials have been reported as nucleic acid delivery systems, lipid nanoparticles have been used in patisiran (ONPATTRO®), an siRNA drug first approved by FDA in 2018, as well as the mRNA vaccine for COVID-19 that was approved for emergency use in 2020. Current lipid nanoparticles are generally used in a form mixed with four components such as an ionized lipid, phospholipid (a helper lipid), cholesterol (a structure-maintaining lipid), and a PEGylated lipid in a certain ratio.

With the commercialization of new siRNA drugs and mRNA vaccines, there are a variety of issues on the lipid nanoparticle-based delivery that need to be addressed, such as targeting, easiness in storage and distribution, mitigation of side effects, cost reduction, and responses to breakthrough infections, in addition to improvement in stability and cell permeability, which are challenges in the field of traditional nucleic acid drug delivery. Therefore, the development of lipid-based deliveries and stabilizers that can solve new challenges is required in the nucleic acid drug market.

An object of the present disclosure is to provide an amphiphilic lipid which is based on Zn(II)-dipicolylamine complex (Zn/DPA) has a water-soluble linker and a hydrophobic terminal, and a lipid nanoparticle composition for nucleic acid delivery comprising the same.

To achieve the above object, the present disclosure provides a compound selected from a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 1, R is a linear or branched, saturated or unsaturated hydrocarbon with 6 to 22 carbon atoms, where the hydrocarbon includes or does not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond is bonded or not bonded to a glycerol structure, and m is an integer of 1 to 10.

The present disclosure provides a compound selected from a compound represented by the following Chemical Formula 7 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 7, Rand Rare the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms, where the hydrocarbon includes or does not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond is bonded or not bonded to a glycerol structure, and n is an integer of 0 to 10.

The present disclosure provides a compound selected from a compound represented by the following Chemical Formula 11 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 11, Rand Rare the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms, where the hydrocarbon includes or does not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond is bonded or not bonded to a glycerol structure.

The present disclosure provides an amphiphilic lipid compound for nucleic acid binding, including the compound.

The present disclosure provides a lipid nanoparticle composition including the amphiphilic lipid compound for nucleic acid binding.

In addition, the present disclosure provides a composition for drug delivery, including the lipid nanoparticle composition; and a therapeutic or prophylactic agent.

A novel compound according to the present disclosure includes a water-soluble linker and a hydrophobic terminal group in Zn/DPA, thereby improving solubility in water.

By utilizing the compound as an amphiphilic lipid compound for nucleic acid binding, it is possible to prepare lipid nanoparticles and deliver nucleic acid drugs more effectively using the same.

Hereinafter, the present disclosure will be described in detail.

The present inventor completed the present disclosure by synthesizing a novel amphiphilic lipid based on Zn(II)-dipicolylamine complex (Zn/DPA) in order to improve shortcomings due to conventional lipid nanoparticles and finding the probability in production of lipid nanoparticles that are capable of appropriately delivering nucleic acid drugs using the same.

The present disclosure provides an amphiphilic lipid compound based on Zn/DPA.

More specifically, the present disclosure provides a compound selected from a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 1, R may be a linear or branched, saturated or unsaturated hydrocarbon with 6 to 22 carbon atoms, where the hydrocarbon may or may not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond may or may not be bonded to a glycerol structure, and m may be selected from integers of 1 to 10.

Preferably, the compound represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 2:

wherein, in the Chemical Formula 2, R′ may be a linear or branched, saturated or unsaturated hydrocarbon with 6 to 22 carbon atoms, where the hydrocarbon may or may not include an ester, ether, amide, carbamate, carbonate, or disulfide bond.

More preferably, the compound represented by Chemical Formula 1 may include any one or more selected from the group consisting of compounds represented by the following Chemical Formula 3 to Chemical Formula 6:

As used herein, the compound represented by Chemical Formula 3 may be named Zn/DPA-PA, the compound represented by Chemical Formula 4 named Zn/DPA-OA, the compound represented by Chemical Formula 5 named Zn/DPA-LA, and the compound represented by Chemical Formula 6 named Zn/DPA-LNA.

The compound represented by the following Chemical Formula 1 according to the present disclosure includes a water-soluble linker and a hydrophobic terminal group in Zn/DPA, thereby improving solubility in water.

The present disclosure provides a compound selected from a compound represented by the following Chemical Formula 7 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 7, Rand Rmay be the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms, where the hydrocarbon may or may not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond may or may not be bonded to a glycerol structure, and n may be selected from integers of 0 to 10.

Preferably, the compound represented by Chemical Formula 7 may be a compound represented by the following Chemical Formula 8:

wherein, in the Chemical Formula 8, Xand X′may be the same or different and each independently CH, NH, or O; Yand Y′may be the same or different and each independently O or S; Zand Z′may be the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms; nmay be an integer of 0 to 5; and oand o′may be the same or different and each independently selected from integers of 2 to 10.

Specifically, in the Chemical Formula 8, Xand X′may be the same or different and each independently CH, NH, or O; Yand Y′may be O; Zand Z′may be the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms; nmay be an integer of 0 to 3; and oand o′may be the same or different and each independently integers of 4 to 8.

More preferably, the compound represented by Chemical Formula 7 may include a compound represented by the following Chemical Formula 9 or Chemical Formula 10:

As used herein, the compound represented by Chemical Formula 9 may be named Zn/DPA-01 and the compound represented by Chemical Formula 10 may be named Zn/DPA-02.

The compound represented by Chemical Formula 7 according to the present disclosure may include a terminal group exhibiting hydrophobicity in Zn/DPA, and the terminal group may have a cone shape to help the endosomal escape of nucleic acids.

In addition, the present disclosure provides a compound selected from a compound represented by the following Chemical Formula 11 or a pharmaceutically acceptable salt thereof:

wherein, in the Chemical Formula 11, Rand Rmay be the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms, where the hydrocarbon may or may not include an ester, ether, amide, carbamate, carbonate, or disulfide bond, and the ester, ether, amide, carbamate, carbonate, or disulfide bond may or may not be bonded to a glycerol structure.

Preferably, the compound represented by Chemical Formula 11 may be a compound represented by the following Chemical Formula 12:

wherein, in the Chemical Formula 12, Xand X′may be the same or different and each independently CH, NH, or O; Yand Ymay be the same or different and each independently O or S; Zand Z′1 may be the same or different and each independently linear or branched, saturated or unsaturated hydrocarbons with 6 to 22 carbon atoms; and 01 and o′1 may be the same or different and each independently selected from integers of 2 to 10.